Ultra-diluted complex additive in the diet reveals benefits in the intestinal tract of nursery-phase piglets.

This study aimed to assess an ultra-diluted (UD) complex, as a replacement for an antimicrobial growth promoter in diets, on growth performance, intestinal health, and inflammatory response of nursery piglets. The experiment lasted 37 days and involved 126 animals weaned at 21 ± 1.3 d, with an initial body weight of 5.62 ± 1.16 kg. Piglets were assigned to six dietary treatments in a randomized block design with seven replicates and three piglets per pen as experimental unit. The treatments were: positive control (PC)- basal diet + 120 mg/kg of chlorohydroxyquinoline; negative control (NC)- basal diet without additives; and NC containing 4.5; 6.0; 7.5 or 9.0 kg of UD additive/ton diet. Performance data were calculated, and daily diarrhea was observed. Blood samples were collected for hematological analysis. At the end of the experiment, one animal per pen was slaughtered for organ weighing, pH, and the collection of intestinal samples for histopathology. Feces and cecal contents were collected for microbiological and antibiogram analyses. There was no difference in the performance between the treatments. Throughout the study, UD levels were equal to those of PC for diarrhea occurrence. Higher levels of UD complex led to higher total leukocyte counts. The 4.5 treatment showed a reduction in total and thermotolerant Enterobacteriaceae populations in piglet feces and an increase in lactic acid bacteria compared to PC. All treatments resulted in fewer duodenal histopathological alterations than those in the NC group. The use of UD additives, especially at 4.5 kg/ton, is a good alternative to chlorohydroxyquinoline in piglet diets.

Correction: Mixed management in growing and finishing pigs: Differences between gender and their impacts on behavior, growth performance, and physiological parameters.

[This corrects the article DOI: 10.1371/journal.pone.0284481.].

Stress response mechanisms in protein misfolding diseases: Profiling a cellular model of Huntington's disease.

Stress response pathways like the integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt) and the heat shock response (HSR) have emerged as part of the pathophysiology of neurodegenerative diseases, including Huntington's disease (HD) - a currently incurable disease caused by the production of mutant huntingtin (mut-Htt). Previous data from HD patients suggest that ISR is activated while UPRmt and HSR are impaired in HD. The study of these stress response pathways as potential therapeutic targets in HD requires cellular models that mimic the activation status found in HD patients of such pathways. PC12 cells with inducible expression of the N-terminal fragment of mut-Htt are among the most used cell lines to model HD, however the activation of stress responses remains unclear in this model. The goal of this study is to characterize the activation of ISR, UPRmt and HSR in this HD cell model and evaluate if it mimics the activation status found in HD patients. We show that PC12 HD cell model presents reduced levels of Hsp90 and mitochondrial chaperones, suggesting an impaired activation or function of HSR and UPRmt. This HD model also presents increased levels of phosphorylated eIF2α, the master regulator of the ISR, but overall similar levels of ATF4 and decreased levels of CHOP - transcription factors downstream to eIF2α - in comparison to control, suggesting an initial activation of ISR. These results show that this model mimics the ISR activation and the impaired UPRmt and HSR found in HD patients. This work suggests that the PC12 N-terminal HD model is suitable for studying the role of stress response pathways in the pathophysiology of HD and for exploratory studies investigating the therapeutic potential of drugs targeting stress responses.

Mixed management in growing and finishing pigs: Differences between gender and their impacts on behavior, growth performance, and physiological parameters.

Mixing, a common management strategy used to regroup pigs, has been reported to impair individual performance and affect pig welfare because of the establishment of a new social hierarchy after regrouping. In this study we aimed to determine whether mixing management (non-mixed vs. mixed) and gender (gilts vs. barrows) affect the social and non-social behavior, performance, and physiological parameters of pigs. A total of 96 growing pigs (48 barrows and 48 females) were separated into two treatments: control (CT)-pigs that were mixed once during the growing-finishing period; and social stress (SS)-pigs that were mixed thrice during the growing-finishing period. We recorded social and non-social behaviors, injury score, performance, and physiological parameters during the experimental period. Data were grouped by the period, based on each mix performed, and overall values. The statistical analysis performed considered gender and treatment. For treatment, during period-II and III, the SS group presented the highest frequency of agonistic interactions (AI), stayed longer lying laterally (LL) and sternly (LS), and explored more enrichment material (ER) than the CT group. Furthermore, SS pigs presented the highest injury score in the ear, head, and middle and posterior regions. Compared to the females, the barrows spent more time at the electronic feed station and initiated most of the agonistic interactions during period-II, and they presented a higher injury score for the ear and head regions during period-III. In conclusion, repeated regrouping significantly affected social and feeding behavior without severely altering performance and physiological parameters. Furthermore, different patterns of social and feeding behavior, agonistic interactions, and injury scores between barrows and females were observed. This study provides an understanding of the impact of mixing management and gender differences on pigs, and this knowledge can be used to improve swine productivity and welfare.

Hierarchy Establishment in Growing Finishing Pigs: Impacts on Behavior, Growth Performance, and Physiological Parameters.

In recent years, an increased number of studies have dealt with the analysis of social dominance related to animal behavior, physiology, and performance. This study aimed to investigate whether hierarchical ranking affects the coping style, non-social behavior during open field and novel object tests, performance, and physiological parameters of pigs. A total of 48 growing pigs (24 barrows and 24 females) were mixed three times during the growing-finishing period. The social and non-social behaviors of pigs were directly noted, and three behavioral tests were performed during the experimental period. Performance and physiological parameters were also recorded. Statistical analysis considered hierarchical classification (dominant vs. intermediary vs. subordinate) and p-values ≤ 0.05 were considered significant. After three regroupings, the pigs in different hierarchical classifications showed no change in hair cortisol values and open-field and novel object tests. Mean corpuscular hemoglobin concentration and leukocyte values increased in intermediary pigs, and the lowest counts were found in pigs classified as dominants. Furthermore, dominant pigs visited the feeder more but spent shorter time there compared to subordinate and intermediary pigs. Our results suggest that hierarchical classification influenced feeding behavior and physiological parameters without affecting cortisol values and growth performance, demonstrating a possible compensation skill.

Binding of common organic UV-filters to the thyroid hormone transport protein transthyretin using in vitro and in silico studies: Potential implications in health.

Several anthropogenic contaminants have been identified as competing with the thyroid hormone thyroxine (T4) for binding to transport proteins as transthyretin (TTR). This binding can potentially create toxicity mechanisms posing a threat to human health. Many organic UV filters (UVFs) and paraben preservatives (PBs), widely used in personal care products, are chemicals of emerging concern due to their adverse effects as potential thyroid-disrupting compounds. Recently, organic UVFs have been found in paired maternal and fetal samples and PBs have been detected in placenta, which opens the possibility of the involvement of TTR in the transfer of these chemicals across physiological barriers. We aimed to investigate a discrete set of organic UVFs and PBs to identify novel TTR binders. The binding affinities of target UVFs towards TTR were evaluated using in vitro T4 competitive binding assays. The ligand-TTR affinities were determined by isothermal titration calorimetry (ITC) and compared with known TTR ligands. In parallel, computational studies were used to predict the 3-D structures of the binding modes of these chemicals to TTR. Some organic UVFs, compounds 2,2',4,4'-tetrahydroxybenzophenone (BP2, Kd = 0.43 µM); 2,4-dihydroxybenzophenone (BP1, Kd = 0.60 µM); 4,4'-dihydroxybenzophenone (4DHB, Kd = 0.83 µM), and 4-hydroxybenzophenone (4HB, Kd = 0.93 µM), were found to display a high affinity to TTR, being BP2 the strongest TTR binder (ΔH = -14.93 Kcal/mol). Finally, a correlation was found between the experimental ITC data and the TTR-ligand docking scores obtained by computational studies. The approach integrating in vitro assays and in silico methods constituted a useful tool to find TTR binders among common organic UVFs. Further studies on the involvement of the transporter protein TTR in assisting the transplacental transfer of these chemicals across physiological barriers and the long-term consequences of prenatal exposure to them should be pursued.

Implementation of an Integrated Lung Cancer Prevention and Screening Program Using a Mobile Computed Tomography (CT) Unit in Brazil.

INTRODUCTION: Lung cancer is the deadliest cancer worldwide and in Brazil. Despite strong evidence, lung cancer screening by low-dose computed tomography (LDCT) in high-risk individuals is far from a reality in many countries, particularly in Brazil. Brazil has a universal public health system marked with important inequalities. One affordable strategy to increase the coverage of resources is to use mobile units. OBJECTIVES: To describe the implementation and results of an innovative lung cancer prevention program that integrates tobacco cessation and lung cancer screening using a mobile CT unit. METHODOLOGY: From May 2019 to Dec 2020, health professionals from 18 public primary health care units in Barretos, Brazil, were trained to offer smoking cessation counseling and treatment. Eligible high-risk participants of this program were also invited to perform lung cancer screening in a mobile LDCT unit that was specially conceived to be dispatched to the community. A detailed epidemiological questionnaire was administered to the LDCT participants. RESULTS: Among the 233 screened participants, the majority were women (54.9%), and the average age was 62 years old. A total of 52.8% of participants showed high or very high nicotine dependence. After 1 year, 27.8% of participants who were involved in smoking cessation groups had quit smoking. The first LDCT round revealed that the majority of participants (83.7%) exhibited lung-Rads 1 or 2; 7.3% exhibited lung-Rads 3; 7.7% exhibited lung-Rads 4a; and 3% exhibited lung-Rads 4b or 4x. The three participants with lung-Rads 4b were further confirmed, and their surgery led to the diagnosis of early-stage cancer (1 case of adenocarcinoma and two cases of squamous cell carcinoma), leading to a cancer diagnosis rate of 12.8/1000. CONCLUSION: Our results indicate promising outcomes for an onsite integrative program enrolling high-risk individuals in a middle-income country. Evidence barriers and challenges remain to be overcome.

An (un)healthy social dilemma: a normative messaging field experiment with flu vaccinations.

BACKGROUND: Influenza seasons can be unpredictable and have the potential to rapidly affect populations, especially in crowded areas. Prior research suggests that normative messaging can be used to increase voluntary provision of public goods, such as the influenza vaccine. We extend the literature by examining the influence of normative messaging on the decision to get vaccinated against influenza. METHODS: We conduct a field experiment in conjunction with University Health Services, targeting undergraduate students living on campus. We use four posters, randomized by living area clusters to advertise flu vaccination clinics during the Fall. The wording on the posters is varied to emphasize the individual benefits of the vaccine, the social benefits of the vaccine or both benefits together. We collect survey data for those vaccinated at the vaccination clinics, and for those not vaccinated via an online survey. RESULTS: We find that any normative message increases the percentage of students getting the flu vaccine compared with no message. In terms of the likelihood of getting the flu vaccine, emphasizing both the individual and social benefits of vaccination has the largest increase in the vaccination rate (19-20 percentage point increase). However, flu vaccinations did not reach the herd immunity threshold (70% of students vaccinated). CONCLUSIONS: This study provides evidence that there is a pro-social component that is relevant in individual vaccination decisions which should be accounted for when designing vaccination campaigns. The results of this normative, pro-social messaging experiment could be extended to other at-risk communities where the number of background risks is much larger. This is especially relevant nowadays, as other seasonal vaccines are being rolled out and younger adults are the ones with the lowest uptake.

Preclinical safety evaluation of the ethanolic extract from the aerial parts of Gomphrena celosioides Mart. in rodents.

The toxicological potential of the ethanolic extract from Gomphrena celosioides (EEGC), a medicinal plant used as a natural analgesic, was investigated in acute and subacute toxicity models in rodents. For the acute toxicity test, 2000 mg/kg of EEGC was administered orally to male and female Wistar rats, while Swiss mice received 75, 150 or 300 mg/kg of EEGC for the subacute toxicity test. Animals treated with an only dose of 2000 mg/kg EEGC showed no clinical signs of toxicity, indicating that the LD50 is higher than this dose. The repeated treatment with EEGC did not cause adverse clinical signs, or lesions in target tissues. According to the Globally Harmonized System of classification, the EEGC dosages can be in Category 5 which is the least toxic or non-toxic one.

Comparative Detection of Immunoglobulin Isotypes and Subclasses against Toxoplasma gondii Soluble Antigen in Serum and Colostrum Samples from Puerperal Women.

BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that can infect several species, including humans, and can cause severe damage to the fetus when the infection occurs during pregnancy. The environment and/or food contamination are critical to spreading the infection. Human milk is rich in nutrients and bioactive elements that provide growth and development of the immune system of the newborn. All isotypes of immunoglobulins are present in human colostrum and they are produced from systemic or local sources. Breastfeeding protects the infant against various pathogens, but there is no conclusive study to detect IgG subclasses in colostrum against T. gondii. Therefore, the aim of this study was to detect and evaluate the presence of antibody isotypes against T. gondii in paired samples of serum and colostrum. METHODS: The study included 283 puerperal patients. ELISA (Enzyme-Linked Immunosorbent Assay) for detection of anti-T. gondii-specific IgM, IgA, and IgG isotypes and IgG1, IgG3, and IgG4 subclasses were conducted on paired samples of serum and colostrum. RESULTS: It was found that 45.9%, 6.0%, and 2.1% of serum samples and 45.2%, 7.1%, and 2.1% of colostrum samples were positive for IgG, IgM, and IgA, respectively. Specific IgG1, IgG3, and IgG4 were positive, respectively, in 98.5%, 54.6%, and 44.6% of serum samples, in contrast with 56.9%, 78.5%, and 34.6% of colostrum samples. Thus, the predominant reactivity of IgG subclasses against T. gondii was IgG1 in serum and IgG3 in colostrum. The higher percentage of positive samples and higher levels of anti-T. gondii IgG3 antibodies were observed in colostrum, when compared to serum samples, suggesting a local production of this subclass. IgG3 and IgG1 subclasses presented different percentages of positivity in serum and colostrum. Only the IgG1 subclass showed a significant correlation between the levels of anti-T. gondii in serum and colostrum, suggesting that IgG1 in breast milk comes from a systemic source. IgG4 showed a similar percentage of positivity in both sample types, but no significant correlation was observed between their levels. CONCLUSION: Colostrum presents representative levels of IgM, IgA, IgG1, IgG3, and IgG4 antibodies specific to T. gondii. The detection of these antibodies presents the potential for diagnostic application of colostrum samples to better identify the diagnostic status of T. gondii infection, especially during the acute phase. In addition, breastfeeding can also be a possible source of protective antibodies for the newborn against toxoplasmosis, an anthropozoonosis maintained by environmental infection, which interferes in the public health of many countries.

Assessing initial plan check efficacy using TG 275 failure modes and incident reporting.

Plan checks are important components of a robust quality assurance (QA) program. Recently, the American Association of Physicists in Medicine (AAPM) published two reports concerning plan and chart checking, Task Group (TG) 275 and Medical Physics Practice Guideline (MPPG) 11.A. The purpose of the current study was to crosswalk initial plan check failure modes revealed in TG 275 against our institutional QA program and local incident reporting data. Ten physicists reviewed 46 high-risk failure modes reported in Table S1.A.i of the TG 275 report. The committee identified steps in our planning process which sufficiently checked each failure mode. Failure modes that were not covered were noted for follow-up. A multidisciplinary committee reviewed the narratives of 1599 locally-reported incidents in our Radiation Oncology Incident Learning System (ROILS) database and categorized each into the high-risk TG 275 failure modes. We found that over half of the 46 high-risk failure modes, six of which were top-ten failure modes, were covered in part by daily contouring peer-review rounds, upstream of the traditional initial plan check. Five failure modes were not adequately covered, three of which concerned pregnancy, pacemakers, and prior dose. Of the 1599 incidents analyzed, 710 were germane to the initial plan check, 23.4% of which concerned missing pregnancy attestations. Most, however, were caught prior to CT simulation (98.8%). Physics review and initial plan check were the least efficacious checks, with error detection rates of 31.8% and 31.3%, respectively, for some failure modes. Our QA process that includes daily contouring rounds resulted in increased upstream error detection. This work has led to several initiatives in the department, including increased automation and enhancement of several policies and procedures. With TG 275 and MPPG 11.A as a guide, we strongly recommend that departments consider an internal chart checking policy and procedure review.

Induced Stress and Tactile Stimulation Applied to Primiparous does and their Consequences on Maternal Behavior, Human-Animal Relationships, and Future Offspring's Sexual Disorders.

The aim of this study was to investigate whether tactile stimulation in rabbits during the gestation phase improve the maternal behavior and human-animal relationships as well as the effects on reproductive behavior of male kits when reached maturity compared to induced stress. A total of 33 primiparous New Zealand does were selected after pregnancy confirmation and allocated in a randomized complete block design. The treatments applied were as follows: (C) animals not stimulated during the experimental period; (TS) animals that received tactile stimulation; and (SS) does which were immobilized. The nest building behavior as well as the weight, sexual behavior, mortality, and semen analysis of the offspring was recorded. In addition, the novel object, flight distance, social isolation, and human-approach tests were conducted. Under the conditions of the present trial, TS animals showed more trust in the unfamiliar observer when compared to the other two treatments. The treatments applied to the females (TS and SS) were sufficient to confirm that the control group presented better values for the number of stillbirths and the proportion of deaths in the first week. Finally, the handling of does reduce the males' ejaculation and sperm presence but not inhibited sexual behavior or impaired semen quality. It is possible to conclude that TS did not impair does welfare or maternal behavior and it improved the human-animal relationship, however there was a negative impact on the litter. More studies that directly assess impact on the future reproductive capacity of the offspring are necessary.

Toxicological evaluation of ethanolic extract of leaves from Doliocarpus dentatus in Swiss mice.

Doliocarpus dentatus (Dilleniaceae) has been used in folk medicine to treat inflammation and pain; however, studies evaluating its toxicity potential, as well as its effects on anxiety and depression, are scarce. This study investigated the toxicological profile of an ethanolic extract from leaves of D. dentatus (EEDd), and its effects on anxiety and depression models in mice. Male and female mice received either a single dose (500, 1000 or 2000 mg/kg) or repeated doses (75, 150 or 300 mg/kg) of EEDd by oral gavage. During the subacute toxicity assay, behavioral tests were performed on days 4, 14, 21 and 28. No evidence of toxicity was observed in the animals in both acute and subacute tests. However, males treated with the highest dose presented a reduction in the absolute weight of the kidney, an elevation in the AST levels, in addition to an alteration in the urea levels. The treatment did not affect other biochemical parameters, and did not induce any depressive-like behavior. EEDd exhibited low toxicity after single and repeated exposures. Since some analyzed parameters were compromised, further toxicity studies should be carried out.

Simultaneous feeding of calcium butyrate and tannin extract decreased the incidence of diarrhea and proinflammatory markers in weaned piglets.

OBJECTIVE: This study was conducted to investigate the effect of associating calcium butyrate with tannin extract, compared to an antimicrobial on the growth performance, incidence of diarrhea, intestinal histology, immune-expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor α (TNF-α) in piglets. METHODS: Seventy-two piglets (36 barrows and 36 gilts) weaned at 28±2 d and initial body weight of 7.17±1.07 kg were allocated to 3 treatments in a randomized complete block design with 8 replicates per treatment and 3 animals per experimental unit. Treatments were composed of NC, negative control: basal diet without additives; PC, positive control: basal diet + 40 mg/kg of colistin sulfate; or BT, basal diet + calcium butyrate + tannin extract. The butyrate and tannin inclusion levels were 0.15% in the pre-starter phase and 0.075% in the starter phase. Incidence of diarrhea was monitored daily, and on d 14 and 35 of experiment, 1 animal from each experimental unit was slaughtered to collect intestinal samples. RESULTS: No significant differences were observed for growth performance. The butyrate-and tannin-based additive resulted in reduced (p<0.05) incidence of diarrhea in piglets during d 1 to 14 and d 1 to 35 in comparison with the other treatments. Piglets that consumed the diet containing the calcium-butyrate and tannin showed a lower (p<0.05) crypt depth in the duodenum than those receiving the NC treatment at 14 d of experimentation. The BT treatment provided a lower (p<0.05) immune-expression of COX-2 at 14 d and TNF-α at 35 d in the duodenum. CONCLUSION: Association between calcium butyrate and tannin extract resulted in a significant decrease in the incidence of diarrhea and inflammatory process in the duodenum of piglets. Therefore, calcium-butyrate combined with tannin could be a part of an alternative program to reduce the use of antimicrobials in the diet of weaned piglets.

Prevalence of Dengue, Chikungunya and Zika Viruses in Blood Donors in the State of Pará, Northern Brazil: 2018-2020.

Arboviruses have been reported over the years as constant threats to blood transfusion recipients, given the high occurrence of asymptomatic cases and the fact that the presence of viremia precedes the onset of symptoms, making it possible that infected blood from donors act as a source of dissemination. This work aims to identify the prevalence of dengue virus (DENV), Zika virus (ZIKV) and Chikungunya virus (CHIKV) infection in blood donors during epidemic and non-epidemic periods; classify the donor as symptomatic or asymptomatic; and verify the need to include DENV, CHIKV and ZIKV in the nucleic acid test (NAT) platform in northern Brazil. We investigated 36,133 thousand donations in two years of collection in Northern Brazil. One donor was positive for DENV and one for CHIKV (0.002% prevalence). As the prevalence for arboviruses was low in this study, it would not justify the individual screening of samples from donors in a blood bank. Thus, DENV- and CHIKV-positive samples were simulated in different amounts of sample pools, and both were safely detected by molecular biology even in a pool of 14 samples, which would meet the need to include these three viruses in the routine of blood centers in endemic countries such as Brazil.

Exploring the Physiological Role of Transthyretin in Glucose Metabolism in the Liver.

Transthyretin (TTR), a 55 kDa evolutionarily conserved protein, presents altered levels in several conditions, including malnutrition, inflammation, diabetes, and Alzheimer's Disease. It has been shown that TTR is involved in several functions, such as insulin release from pancreatic ß-cells, recovery of blood glucose and glucagon levels of the islets of Langerhans, food intake, and body weight. Here, the role of TTR in hepatic glucose metabolism was explored by studying the levels of glucose in mice with different TTR genetic backgrounds, namely with two copies of the TTR gene, TTR+/+; with only one copy, TTR+/-; and without TTR, TTR-/-. Results showed that TTR haploinsufficiency (TTR+/-) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4. Further, we showed that TTR haploinsufficiency decreases pyruvate kinase M type (PKM) levels in mice livers, by qRT-PCR, but it does not affect the hepatic production of the studied metabolites, as determined by 1H NMR. Finally, we demonstrated that TTR increases mitochondrial density in HepG2 cells and that TTR insufficiency triggers a higher degree of oxidative phosphorylation in the liver. Altogether, these results indicate that TTR contributes to the homeostasis of glucose by regulating the levels of glucose transporters and PKM enzyme and by protecting against mitochondrial oxidative stress.

Soybean meal and poultry offal meal effects on digestibility of adult dogs diets: Systematic review.

Soybean meal and poultry offal meal are protein ingredients commonly used in the formulation of commercial diets for dogs. However, there remains great variability in the data on the digestibility of each protein source. This systematic review study aimed to examine the intake, apparent nutrient digestibility coefficients and fecal output of protein sources (soybean meal and poultry offal meal) in adult dog food as reported in published studies. The article search was conducted in August 2018 in the PUBMED, SciELO, Science Direct and AGRIS indexing databases. The literature search was performed using "digestibility", "source protein" and "dog" as the main key terms combined with sub-terms to broaden the scope of the search. Criteria were defined for readability, exclusion and inclusion of articles. Results were organized in groups according to the search in the indexing databases, totaling 1,414 articles. After the works were selected following the inclusion criteria, 17 articles were evaluated in this review. According to most studies, plant-based ingredients have a less variable nutritional composition than animal-derived ingredients and poultry offal meal increases the digestibility coefficients of nutrients and energy and reduces fecal dry matter production. Factors inherent to raw-material origin, ingredient and food processing, as well as the high heterogeneity of the methodologies evaluated in the studies are directly related to the obtained results. To ensure a more accurate evaluation of the quality and of effects on the digestibility of protein sources, we recommended that articles include ingredient processing data and that the variables be evaluated under standardized study conditions.

In-depth transcriptome reveals the potential biotechnological application of Bothrops jararaca venom gland.

BACKGROUND: Lack of complete genomic data of Bothrops jararaca impedes molecular biology research focusing on biotechnological applications of venom gland components. Identification of full-length coding regions of genes is crucial for the correct molecular cloning design. METHODS: RNA was extracted from the venom gland of one adult female specimen of Bothrops jararaca. Deep sequencing of the mRNA library was performed using Illumina NextSeq 500 platform. De novo assembly of B. jararaca transcriptome was done using Trinity. Annotation was performed using Blast2GO. All predicted proteins after clustering step were blasted against non-redundant protein database of NCBI using BLASTP. Metabolic pathways present in the transcriptome were annotated using the KAAS-KEGG Automatic Annotation Server. Toxins were identified in the B. jararaca predicted proteome using BLASTP against all protein sequences obtained from Animal Toxin Annotation Project from Uniprot KB/Swiss-Pro database. Figures and data visualization were performed using ggplot2 package in R language environment. RESULTS: We described the in-depth transcriptome analysis of B. jararaca venom gland, in which 76,765 de novo assembled isoforms, 96,044 transcribed genes and 41,196 unique proteins were identified. The most abundant transcript was the zinc metalloproteinase-disintegrin-like jararhagin. Moreover, we identified 78 distinct functional classes of proteins, including toxins, inhibitors and tumor suppressors. Other venom proteins identified were the hemolytic lethal factors stonustoxin and verrucotoxin. CONCLUSION: It is believed that the application of deep sequencing to the analysis of snake venom transcriptomes may represent invaluable insight on their biotechnological potential focusing on candidate molecules.

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer.

Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

Analysis of the scale of impairment to the application of social technology / Análise da escala de impedimentos à aplicação da tecnologia social / Análisis de la escala de impedimentos a la aplicación de la tecnología social

The process of evaluating the effectiveness of Social Technology for Professional Qualification requires reliable and compact instruments. Therefore, the present study aims to evaluate evidence of the validity of an impairment scale to the Application of Social Technology. The sample consisted of 299 professionals working in public institutions attending people under conditions of social vulnerability in the State of Rio Grande do Sul. The exploratory analysis of graph data suggested a structure with three factors: interpersonal relationship, infrastructure, and perceptions of work with vulnerable populations. The confirmatory factor analysis presented low residue indexes and excellent fit indices. The results demonstrate the adequacy of the scale to investigate factors that impair the application of the contents of professional training.

O processo de avaliação da efetividade de uma Tecnologia Social para Capacitação Profissional necessita de instrumentos fidedignos e breves. Com base nisso, o presente estudo objetiva avaliar evidências de validade de uma Escala de Impedimentos à Aplicação da Tecnologia Social. A amostra foi composta por 299 profissionais que trabalham em instituições públicas de atendimento às populações em vulnerabilidade social no estado do Rio Grande do Sul. A análise exploratória de grafos sugeriu uma estrutura com três fatores: relacionamento interpessoal, infraestrutura e percepções do trabalho com populações vulneráveis. A análise fatorial confirmatória apresentou baixos índices de resíduos e excelentes índices de ajuste. Os resultados demonstram a adequação da escala para investigar fatores impeditivos à aplicação dos conteúdos trabalhados em capacitações profissionais

El proceso de evaluación de la efectividad de una Tecnología Social de Capacitación Profesional necesita instrumentos fidedignos y breves. Con base en ello, el presente estudio objetiva evaluar evidencias de validez de una Escala de Impedimentos a la Aplicación de la Tecnología Social. La muestra fue compuesta por 299 profesionales que trabajan en instituciones públicas de atención a las poblaciones en vulnerabilidad social en el estado de Rio Grande do Sul. El análisis exploratorio de grafos sugirió una estructura con tres factores: relación interpersonal, infraestructura y percepciones del trabajo con poblaciones vulnerables. El análisis factorial confirmatorio presentó bajos índices de residuos y excelentes índices de ajuste. Los resultados demuestran la adecuación de la escala para investigar factores impeditivos a la aplicación de los contenidos trabajados en capacitaciones profesionales.